Targeting metabotropic glutamate receptors in the treatment of epilepsy: rationale and current status

References

• Tsai JJ, Wu T, Leung H, et al. Perampanel, an AMPA receptor antagonist: from clinical research to practice in clinical settings. Acta Neurol Scand. 2018 Apr;137(4):378–391.
   PubMed Web of Science ®Google Scholar
• Mayer ML, Westbrook GL. Permeation and block of N-methyl-D-aspartic acid receptor channels by divalent cations in mouse cultured central neurones. J Physiol. 1987 Dec;394:501–527.
   PubMed Web of Science ®Google Scholar
• Johnson JW, Ascher P. Glycine potentiates the NMDA response in cultured mouse brain neurons. Nature. 1987 Feb 5–11;325(6104):529–531.
   PubMed Web of Science ®Google Scholar
• Collingridge GL, Bliss TV. Memories of NMDA receptors and LTP. Trends Neurosci. 1995 Feb;18(2):54–56.
   PubMed Web of Science ®Google Scholar
• Meador KJ. The basic science of memory as it applies to epilepsy. Epilepsia. 2007;48(Suppl 9):23–25.
   PubMedGoogle Scholar
• Meldrum BS. The role of glutamate in epilepsy and other CNS disorders. Neurology. 1994 Nov;44(11 Suppl 8):S14–23.
   PubMed Web of Science ®Google Scholar
• Lodge D, Mercier MS. Ketamine and phencyclidine: the good, the bad and the unexpected. Br J Pharmacol. 2015 Sep;172(17):4254–4276.
   PubMed Web of Science ®Google Scholar
• Bruno V, Battaglia G, Copani A, et al. Metabotropic glutamate receptor subtypes as targets for neuroprotective drugs. J Cereb Blood Flow Metab. 2001 Sep;21(9):1013–1033.
   PubMed Web of Science ®Google Scholar
• Nicoletti F, Bockaert J, Collingridge GL, et al. Metabotropic glutamate receptors: from the workbench to the bedside. Neuropharmacology. 2011 Jun;60(7–8):1017–1041.
   PubMed Web of Science ®Google Scholar
• Niswender CM, Conn PJ. Metabotropic glutamate receptors: physiology, pharmacology, and disease. Annu Rev Pharmacol Toxicol. 2010;50:295–322.
   PubMed Web of Science ®Google Scholar
• Conn PJ, Pin JP. Pharmacology and functions of metabotropic glutamate receptors. Annu Rev Pharmacol Toxicol. 1997;37:205–237.
   PubMed Web of Science ®Google Scholar
• Di Menna L, Joffe ME, Iacovelli L, et al. Functional partnership between mGlu3 and mGlu5 metabotropic glutamate receptors in the central nervous system. Neuropharmacology. 2018 Jan;128:301–313.
   PubMed Web of Science ®Google Scholar
• Pinheiro PS, Mulle C. Presynaptic glutamate receptors: physiological functions and mechanisms of action. Nat Rev Neurosci. 2008 Jun;9(6):423–436.
   PubMed Web of Science ®Google Scholar
• Feng Z, Ma S, Hu G, et al. Allosteric binding site and activation mechanism of class C G-protein coupled receptors: metabotropic glutamate receptor family. Aaps J. 2015 May;17(3):737–753.
   PubMed Web of Science ®Google Scholar
• Kunishima N, Shimada Y, Tsuji Y, et al. Structural basis of glutamate recognition by a dimeric metabotropic glutamate receptor. Nature. 2000 Oct 26;407(6807):971–977.
   PubMed Web of Science ®Google Scholar
• Muto T, Tsuchiya D, Morikawa K, et al. Structures of the extracellular regions of the group II/III metabotropic glutamate receptors. Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):3759–3764.
   PubMed Web of Science ®Google Scholar
• Nicoletti F, Bruno V, Ngomba RT, et al. Metabotropic glutamate receptors as drug targets: what’s new? Curr Opin Pharmacol. 2015;20:89–94.
   PubMed Web of Science ®Google Scholar
• Rout SK, Kar DM. A review on antiepileptic agents, current research and future prospectus on conventional and traditional drugs. Int J Pharma Sci Rev Res. 2010;3:19-23.
   Google Scholar
• Anovadiya AP, Sanmukhani JJ, Tripathi CB. Epilepsy: novel therapeutic targets. J Pharmacol Pharmacother. 2012 Apr;3(2):112–117.
   PubMedGoogle Scholar
• Lasoń W, Chlebicka M, Rejdak K. Research advances in basic mechanisms of seizures and antiepileptic drug action. Pharmacol Rep. 2013;65(4):787–801.
   PubMed Web of Science ®Google Scholar
• Hovelsø N, Sotty F, Montezinho LP, et al. Therapeutic potential of metabotropic glutamate receptor modulators. Curr Neuropharmacol. 2012 Mar;10(1):12–48.
   PubMed Web of Science ®Google Scholar
• Chapman AG. Glutamate receptors in epilepsy. Prog Brain Res. 1998;116:371–383.
   PubMed Web of Science ®Google Scholar
• Moldrich RX, Beart PM. Emerging signalling and protein interactions mediated via metabotropic glutamate receptors. Curr Drug Targets CNS Neurol Disord. 2003 Apr;2(2):109–122.
   PubMedGoogle Scholar
• Bruno V, Caraci F, Copani A, et al. The impact of metabotropic glutamate receptors into active neurodegenerative processes: A “dark side” in the development of new symptomatic treatments for neurologic and psychiatric disorders. Neuropharmacology. 2017 Mar;15(115):180–192.
   Google Scholar
• Werner FM, Coveñas R. Classical neurotransmitters and neuropeptides involved in generalized epilepsy: a focus on antiepileptic drugs. Curr Med Chem. 2011;18(32):4933–4948.
   PubMed Web of Science ®Google Scholar
• Werner FM, Coveñas R. Classical neurotransmitters and neuropeptides involved in generalized epilepsy in a multi-neurotransmitter system: how to improve the antiepileptic effect? Epilepsy Behav. 2017 Jun;71(Pt B):124–129.
   PubMedGoogle Scholar
• Qian F, Tang FR. Metabotropic glutamate receptors and interacting proteins in epileptogenesis. Curr Neuropharmacol. 2016;14(5):551–562.
   PubMed Web of Science ®Google Scholar
• Tang FR, Bradford HF, Ling EA. Metabotropic glutamate receptors in the control of neuronal activity and as targets for development of anti-epileptogenic drugs. Curr Med Chem. 2009;16(17):2189–2204.
   PubMed Web of Science ®Google Scholar
• Alexander GM, Godwin DW. Metabotropic glutamate receptors as a strategic target for the treatment of epilepsy. Epilepsy Res. 2006 Sep;71(1):1–22.
   PubMed Web of Science ®Google Scholar
• Ure J, Baudry M, Perassolo M. Metabotropic glutamate receptors and epilepsy. J Neurol Sci. 2006 Aug 15;247(1):1–9. Epub 2006 May 11.
   PubMed Web of Science ®Google Scholar
• Moldrich RX, Chapman AG, De Sarro G, et al. Glutamate metabotropic receptors as targets for drug therapy in epilepsy. Eur J Pharmacol. 2003 Aug 22;476(1-2):3-16.
   Google Scholar
• Doherty J, Dingledine R. The roles of metabotropic glutamate receptors in seizures and epilepsy. Curr Drug Targets CNS Neurol Disord. 2002 Jun;1(3):251–260.
   PubMedGoogle Scholar
• Wong RK, Bianchi R, Taylor GW, et al. Role of metabotropic glutamate receptors in epilepsy. Adv Neurol. 1999;79:685–698.
   PubMedGoogle Scholar
• Aronica E, van Vliet EA, Mayboroda OA, et al. Upregulation of metabotropic glutamate receptor subtype mGluR3 and mGluR5 in reactive astrocytes in a rat model of mesial temporal lobe epilepsy. Eur J Neurosci. 2000 Jul;12(7):2333–2344.
   PubMed Web of Science ®Google Scholar
• Tang FR, Lee WL, Yeo TT. Expression of the group I metabotropic glutamate receptor in the hippocampus of patients with mesial temporal lobe epilepsy. J Neurocytol. 2001 May;30(5):403–411.
   PubMedGoogle Scholar
• Blümcke I, Becker AJ, Klein C, et al. Temporal lobe epilepsy associated up-regulation of metabotropic glutamate receptors: correlated changes in mGluR1 mRNA and protein expression in experimental animals and human patients. J Neuropathol Exp Neurol. 2000 Jan;59(1):1–10.
   PubMed Web of Science ®Google Scholar
• Notenboom RG, Hampson DR, Jansen GH, et al. Up-regulation of hippocampal metabotropic glutamate receptor 5 in temporal lobe epilepsy patients. Brain. 2006 Jan;129(Pt 1):96–107.
   PubMedGoogle Scholar
• Kandratavicius L, Rosa-Neto P, Monteiro MR, et al. Distinct increased metabotropic glutamate receptor type 5 (mGluR5) in temporal lobe epilepsy with and without hippocampal sclerosis. Hippocampus. 2013 Dec;23(12):1212–1230.
   PubMed Web of Science ®Google Scholar
• Chapman AG, Yip PK, Yap JS, et al. Anticonvulsant actions of LY 367385 ((+)-2-methyl-4-carboxyphenylglycine) and AIDA ((RS)-1-aminoindan-1,5-dicarboxylic acid). Eur J Pharmacol. 1999 Feb 26;368(1):17–24.
   PubMed Web of Science ®Google Scholar
• Chapman AG, Nanan K, Williams M, et al. Anticonvulsant activity of two metabotropic glutamate group I antagonists selective for the mGlu5 receptor: 2-methyl-6-(phenylethynyl)-pyridine (MPEP), and (E)-6-methyl-2-styryl-pyridine (SIB 1893). Neuropharmacology. 2000 Jul 10;39(9):1567–1574.
   PubMed Web of Science ®Google Scholar
• Borowicz KK, Łuszczki JJ, Czuczwar SJ. 2-Methyl-6-phenylethynyl-pyridine (MPEP), a non-competitive mGluR5 antagonist, differentially affects the anticonvulsant activity of four conventional antiepileptic drugs against amygdala-kindled seizures in rats. Pharmacol Rep. 2009 Jul-Aug;61(4):621–630.
   PubMed Web of Science ®Google Scholar
• Kingston AE, Griffey K, Johnson MP, et al. Inhibition of group I metabotropic glutamate receptor responses in vivo in rats by a new generation of carboxyphenylglycine-like amino acid antagonists. Neurosci Lett. 2002 Sep 20;330(2):127–130.
   PubMed Web of Science ®Google Scholar
• Zavala-Tecuapetla C, Kubová H, Otáhal J, et al. Age-dependent suppression of hippocampal epileptic afterdischarges by metabotropic glutamate receptor 5 antagonist MTEP. Pharmacol Rep. 2014 Oct;66(5):927–930.
   PubMed Web of Science ®Google Scholar
• Bashkatova VG, Sudakov SK, Prast H. Antagonists of metabotropic glutamate receptors prevent the development of audiogenic seizures. Bull Exp Biol Med. 2015 May;159(1):1–3.
   PubMed Web of Science ®Google Scholar
• Suzuki T, Shimizu N, Tsuda M, et al. Role of metabotropic glutamate receptors in the hypersusceptibility to pentylenetetrazole-induced seizure during diazepam withdrawal. Eur J Pharmacol. 1999 Mar 19;369(2):163–168.
   PubMed Web of Science ®Google Scholar
• Löscher W, Dekundy A, Nagel J, et al. mGlu1 and mGlu5 receptor antagonists lack anticonvulsant efficacy in rodent models of difficult-to-treat partial epilepsy. Neuropharmacology. 2006 Jun;50(8):1006–1015.
   PubMed Web of Science ®Google Scholar
• Witkin JM, Baez M, Yu J, et al. mGlu5 receptor deletion does not confer seizure protection to mice. Life Sci. 2008 Aug 29;83(9–10):377–380.
   PubMed Web of Science ®Google Scholar
• Blumenfeld H. Cellular and network mechanisms of spike-wave seizures. Epilepsia. 2005;46(Suppl 9):21–33.
   PubMedGoogle Scholar
• Schridde U, van Luijtelaar G. The role of the environment on the development of spike-wave discharges in two strains of rats. Physiol Behav. 2005 Mar 16;84(3):379–386.
   PubMed Web of Science ®Google Scholar
• van Luijtelaar G, Sitnikova E, Luttjohann A. On the origin and suddenness of absences in genetic absence models. Clin EEG Neurosci. 2011 Apr;42(2):83–97.
   PubMed Web of Science ®Google Scholar
• Ngomba RT, Santolini I, Biagioni F, et al. Protective role for type-1 metabotropic glutamate receptors against spike and wave discharges in the WAG/Rij rat model of absence epilepsy. Neuropharmacology. 2011 Jun;60(7–8):1281–1291.
   PubMed Web of Science ®Google Scholar
• Karimzadeh F, Modarres Mousavi SM, Ghadiri T, et al. The modulatory effect of metabotropic glutamate receptor type-1α on spike-wave discharges in WAG/Rij rats. Mol Neurobiol. 2017 Mar;54(2):846–854.
   PubMed Web of Science ®Google Scholar
• Guo F, Sun F, Yu JL, et al. Abnormal expressions of glutamate transporters and metabotropic glutamate receptor 1 in the spontaneously epileptic rat hippocampus. Brain Res Bull. 2010 Mar 16;81(4–5):510–516.
   PubMed Web of Science ®Google Scholar
• D’Amore V, Santolini I, Celli R, et al. Head-to head comparison of mGlu1 and mGlu5 receptor activation in chronic treatment of absence epilepsy in WAG/Rij rats. Neuropharmacology. 2014;85:91–103.
   PubMed Web of Science ®Google Scholar
• D’Amore V, Santolini I, van Rijn CM, et al. Potentiation of mGlu5 receptors with the novel enhancer, VU0360172, reduces spontaneous absence seizures in WAG/Rij rats. Neuropharmacology. 2013 Mar;66:330–338.
   PubMed Web of Science ®Google Scholar
• D’Amore V, von Randow C, Nicoletti F, et al. Anti-absence activity of mGlu1 and mGlu5 receptor enhancers and their interaction with a GABA reuptake inhibitor: effect of local infusions in the somatosensory cortex and thalamus. Epilepsia. 2015 Jul;56(7):1141–1151.
   PubMed Web of Science ®Google Scholar
• Lojková D, Mares P. Anticonvulsant action of an antagonist of metabotropic glutamate receptors mGluR5 MPEP in immature rats. Neuropharmacology. 2005;49(Suppl 1):219–229.
   PubMedGoogle Scholar
• Bruno V, Battaglia G, Casabona G, et al. Neuroprotection by glial metabotropic glutamate receptors is mediated by transforming growth factor-beta. J Neurosci. 1998 Dec 1;18(23):9594–9600.
   PubMed Web of Science ®Google Scholar
• Aronica E, Yankaya B, Jansen GH, et al. Ionotropic and metabotropic glutamate receptor protein expression in glioneuronal tumours from patients with intractable epilepsy. Neuropathol Appl Neurobiol. 2001 Jun;27(3):223–237.
   PubMed Web of Science ®Google Scholar
• Aronica E, Gorter JA, Jansen GH, et al. Expression and cell distribution of group I and group II metabotropic glutamate receptor subtypes in taylor-type focal cortical dysplasia. Epilepsia. 2003 Jun;44(6):785–795.
   PubMed Web of Science ®Google Scholar
• Garrido-Sanabria ER, Otalora LF, Arshadmansab MF, et al. Impaired expression and function of group II metabotropic glutamate receptors in pilocarpine-treated chronically epileptic rats. Brain Res. 2008;1240:165–176.
   PubMed Web of Science ®Google Scholar
• Ermolinsky B, Pacheco Otalora LF, Arshadmansab MF, et al. Differential changes in mGlu2 and mGlu3 gene expression following pilocarpine-induced status epilepticus: a comparative real-time PCR analysis. Brain Res. 2008;1226:173–180.
   PubMed Web of Science ®Google Scholar
• Dalby NO, Thomsen C. Modulation of seizure activity in mice by metabotropic glutamate receptor ligands. J Pharmacol Exp Ther. 1996;276(2):516–522.
   PubMed Web of Science ®Google Scholar
• Attwell PJ, Singh Kent N, Jane DE, et al. Anticonvulsant and glutamate release-inhibiting properties of the highly potent metabotropic glutamate receptor agonist (2S,2ʹR, 3ʹR)-2-(2ʹ,3ʹ-dicarboxycyclopropyl)glycine (DCG-IV). Brain Res. 1998 Sep 14;805(1–2):138–143.
   PubMed Web of Science ®Google Scholar
• Miyamoto M, Ishida M, Shinozaki H. Anticonvulsive and neuroprotective actions of a potent agonist (DCG-IV) for group II metabotropic glutamate receptors against intraventricular kainate in the rat. Neuroscience. 1997;77(1):131–140.
   PubMed Web of Science ®Google Scholar
• Caulder EH, Riegle MA, Godwin DW. Activation of group 2 metabotropic glutamate receptors reduces behavioral and electrographic correlates of pilocarpine induced status epilepticus. Epilepsy Res. 2014 Feb;108(2):171–181.
   PubMed Web of Science ®Google Scholar
• Swanson CJ, Bures M, Johnson MP, et al. Metabotropic glutamate receptors as novel targets for anxiety and stress disorders. Nat Rev Drug Discov. 2005 Feb;4(2):131–144.
   PubMed Web of Science ®Google Scholar
• Zhang H, Cilz NI, Yang C, et al. Depression of neuronal excitability and epileptic activities by group II metabotropic glutamate receptors in the medial entorhinal cortex. Hippocampus. 2015 Nov;25(11):1299–1313.
   PubMed Web of Science ®Google Scholar
• Kłodzińska A, Bijak M, Chojnacka-Wójcik E, et al. Roles of group II metabotropic glutamate receptors in modulation of seizure activity. Naunyn Schmiedebergs Arch Pharmacol. 2000 Mar;361(3):283–288.
   PubMed Web of Science ®Google Scholar
• Yao H, Feng YB, Pang YJ, et al. Inhibitory effect of group II mGluR agonist 2R, 4R-APDC on cell proliferation in dentate gyrus in rats with epileptic seizure. Eur Rev Med Pharmacol Sci. 2015 Aug;19(15):2922–2927.
   PubMed Web of Science ®Google Scholar
• Metcalf CS, Klein BD, Smith MD, et al. Efficacy of mGlu(2) -positive allosteric modulators alone and in combination with levetiracetam in the mouse 6 Hz model of psychomotor seizures. Epilepsia. 2017 Mar;58(3):484–493.
   PubMed Web of Science ®Google Scholar
• Metcalf CS, Klein BD, Smith MD, et al. Potent and selective pharmacodynamic synergy between the metabotropic glutamate receptor subtype 2-positive allosteric modulator JNJ-46356479 and levetiracetam in the mouse 6-Hz (44-mA) model. Epilepsia. 2018 Mar;59(3):724–735.
   PubMed Web of Science ®Google Scholar
• Moldrich RX, Jeffrey M, Talebi A, et al. Anti-epileptic activity of group II metabotropic glutamate receptor agonists (–)-2-oxa-4-aminobicyclo[3.1.0] hexane-4,6-dicarboxylate (LY379268) and (–)-2-thia-4-aminobicyclo [3.1.0]hexane-4,6-dicarboxylate (LY389795). Neuropharmacology. 2001;41(1):8–18.
   PubMed Web of Science ®Google Scholar
• Ngomba RT, Biagioni F, Casciato S, et al. The preferential mGlu2/3 receptor antagonist, LY341495, reduces the frequency of spike-wave discharges in the WAG/Rij rat model of absence epilepsy. Neuropharmacology. 2005;49(Suppl 1):89–103.
   PubMedGoogle Scholar
• Mercier MS, Lodge D. Group III metabotropic glutamate receptors: pharmacology, physiology and therapeutic potential. Neurochem Res. 2014 Oct;39(10):1876–1894.
   PubMed Web of Science ®Google Scholar
• Chen J, Larionov S, Pitsch J, et al. Expression analysis of metabotropic glutamate receptors I and III in mouse strains with different susceptibility to experimental temporal lobe epilepsy. Neurosci Lett. 2005 Mar 3;375(3):192–197.
   PubMed Web of Science ®Google Scholar
• Ghauri M, Chapman AG, Meldrum BS. Convulsant and anticonvulsant actions of agonists and antagonists of group III mGluRs. Neuroreport. 1996 Jun 17;7(9):1469–1474.
   PubMed Web of Science ®Google Scholar
• Szczurowska E, Mareš P. Positive allosteric modulator of mGluR4 PHCCC exhibits proconvulsant action in three models of epileptic seizures in immature rats. Physiol Res. 2012;61(6):619–628.
   PubMed Web of Science ®Google Scholar
• Chapman AG, Talebi A, Yip PK, et al. Anticonvulsant activity of a mGlu(4alpha) receptor selective agonist, (1S,3R,4S)-1-aminocyclopentane-1,2,4-tricarboxylic acid. Eur J Pharmacol. 2001 Jul 20;424(2):107–113.
   PubMed Web of Science ®Google Scholar
• Sansig G, Bushell TJ, Clarke VR, et al. Increased seizure susceptibility in mice lacking metabotropic glutamate receptor 7. J Neurosci. 2001 Nov 15;21(22):8734–8745.
   PubMed Web of Science ®Google Scholar
• Folbergrová J, Druga R, Haugvicová R, et al. Anticonvulsant and neuroprotective effect of (S)-3,4-dicarboxyphenylglycine against seizures induced in immature rats by homocysteic acid. Neuropharmacology. 2008 Mar;54(4):665–675.
   PubMed Web of Science ®Google Scholar
• Kral T, Erdmann E, Sochivko D, et al. Down-regulation of mGluR8 in pilocarpine epileptic rats. Synapse. 2003 Mar 15;47(4):278–284.
   PubMed Web of Science ®Google Scholar
• Ngomba RT, Santolini I, Salt TE, et al. Metabotropic glutamate receptors in the thalamocortical network: strategic targets for the treatment of absence epilepsy. Epilepsia. 2011 Jul;52(7):1211–1222.
   PubMed Web of Science ®Google Scholar
• Snead OC 3rd, Banerjee PK, Burnham M, et al. Modulation of absence seizures by the GABA(A) receptor: a critical role for metabotropic glutamate receptor 4 (mGluR4). J Neurosci. 2000 Aug 15;20(16):6218–6224.
   PubMed Web of Science ®Google Scholar
• Ngomba RT, Ferraguti F, Badura A, et al. Positive allosteric modulation of metabotropic glutamate 4 (mGlu4) receptors enhances spontaneous and evoked absence seizures. Neuropharmacology. 2008 Feb;54(2):344–354.
   PubMed Web of Science ®Google Scholar
• Muhle H, von Spiczak S, Gaus V, et al. Role of GRM4 in idiopathic generalized epilepsies analysed by genetic association and sequence analysis. Epilepsy Res. 2010 May;89(2–3):319–326.
   PubMed Web of Science ®Google Scholar
• Parihar R, Mishra R, Singh SK, et al. Association of the GRM4 gene variants with juvenile myoclonic epilepsy in an Indian population. J Genet. 2014 Apr;93(1):193–197.
   PubMed Web of Science ®Google Scholar
• Santos BPD, Marinho CRM, Marques TEBS, et al. Genetic susceptibility in juvenile myoclonic epilepsy: systematic review of genetic association studies. PLoS One. 2017 Jun 21;12(6):e0179629.
   PubMed Web of Science ®Google Scholar
• Bertaso F, Zhang C, Scheschonka A, et al. PICK1 uncoupling from mGluR7a causes absence-like seizures. Nat Neurosci. 2008 Aug;11(8):940–948.
   PubMed Web of Science ®Google Scholar
• Zhang CS, Bertaso F, Eulenburg V, et al. Knock-in mice lacking the PDZ-ligand motif of mGluR7a show impaired PKC-dependent autoinhibition of glutamate release, spatial working memory deficits, and increased susceptibility to pentylenetetrazol. J Neurosci. 2008 Aug 20;28(34):8604–8614.
   PubMed Web of Science ®Google Scholar
• Tassin V, Girard B, Chotte A, et al. Phasic and tonic mGlu7 receptor activity modulates the thalamocortical network. Front Neural Circuits. 2016 Apr 25;10:31.
   PubMed Web of Science ®Google Scholar
• Kyuyoung CL, Huguenard JR. Modulation of short-term plasticity in the corticothalamic circuit by group III metabotropic glutamate receptors. J Neurosci. 2014 Jan 8;34(2):675–687.
   PubMed Web of Science ®Google Scholar
• Swedberg MD, Raboisson P. AZD9272 and AZD2066: selective and highly central nervous system penetrant mGluR5 antagonists characterized by their discriminative effects. J Pharmacol Exp Ther. 2014 Aug;350(2):212–222.
   PubMed Web of Science ®Google Scholar
• Rook JM, Xiang Z, Lv X, et al. Biased mGlu5-positive allosteric modulators provide in vivo efficacy without potentiating mGlu5 modulation of NMDAR currents. Neuron. 2015 May 20;86(4):1029–1040.
   PubMed Web of Science ®Google Scholar
• Russo E, Citraro R, Constanti A, et al. Upholding WAG/Rij rats as a model of absence epileptogenesis: hidden mechanisms and a new theory on seizure development. Neurosci Biobehav Rev. 2016;71:388–408.
   PubMed Web of Science ®Google Scholar
• Childress ES, Wieting JM, Felts AS, et al. Discovery of novel central nervous system penetrant metabotropic glutamate receptor subtype 2 (mGlu(2)) Negative Allosteric Modulators (NAMs) Based on Functionalized Pyrazolo[1,5- a]pyrimidine-5-carboxamide and Thieno[3,2- b]pyridine-5-carboxamide cores. J Med Chem. 2018 Oct 31;62(1).
   Web of Science ®Google Scholar
• Engers JL, Bollinger KA, Weiner RL, et al. Design and synthesis of N-Aryl Phenoxyethoxy Pyridinones as Highly Selective and CNS Penetrant mGlu(3) NAMs. ACS Med Chem Lett. 2017 Aug 15;8(9):925–930.
   PubMed Web of Science ®Google Scholar
• Bollinger KA, Felts AS, Brassard CJ, et al. Design and synthesis of mGlu(2) NAMs with improved potency and CNS penetration based on a truncated picolinamide core. ACS Med Chem Lett. 2017 Aug 3;8(9):919–924.
   PubMed Web of Science ®Google Scholar
• Engers JL, Rodriguez AL, Konkol LC, et al. Discovery of a selective and CNS penetrant negative allosteric modulator of metabotropic glutamate receptor subtype 3 with antidepressant and anxiolytic activity in rodents. J Med Chem. 2015 Sep 24;58(18):7485–7500.
   PubMed Web of Science ®Google Scholar
• Kano M, Watanabe T. Type-1 metabotropic glutamate receptor signaling in cerebellar Purkinje cells in health and disease. F1000Res. 2017 Apr 4;6:416.
   PubMedGoogle Scholar
• Ngomba RT, van Luijtelaar G. Metabotropic glutamate receptors as drug targets for the treatment of absence epilepsy. Curr Opin Pharmacol. 2018 Feb;38:43–50.
   PubMed Web of Science ®Google Scholar